Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance.
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ABSTRACT:
SUBMITTER: Scheller M
PROVIDER: S-EPMC3804946 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesN6-methyladenosine (m6A) is a ubiquitous epigenetic RNA modification that plays a pivotal role in tumour development and metastasis. In this study, we aimed to investigate the expression profiling, clinical significance, biological function and the regulation of m6A-related genes in hepatoblastoma (HB).Materials and methodsThe mRNA and protein expression levels of m6A-related genes were analysed using Gene Expression Omnibus (GEO) and tissue microarray (TMA) cohort. Kaplan-Meier analysis was performed to evaluate the prognostic value of m6A-related genes in HB. Knockdown of m6A-related genes was conducted to analyse its function on cell proliferation, migration and invasion. Furthermore, bioinformatics analysis and experimental verification were used to explore the potential molecular mechanism and signalling pathway.ResultsWe found that most m6A-related genes were significantly upregulated in HB tumour tissues. High levels of methyltransferase-like 3 (METTL3, P = .013), YTHDF2 (P = .037) and FTO (P = .032) indicated poor clinical outcomes, and the upregulation of METTL3 was an independent prognostic factor in HB patients. Functional assays showed that knockdown of METTL3 could dramatically suppress the proliferation, migration and invasion of HB cells. In addition, METTL3 was identified to be a direct target of microRNA-186 (miR-186). Consistently, miR-186 was low expressed in HB tumour tissues. Moreover, overexpression of miR-186 significantly inhibited cell aggressive phenotype both in vitro and in vivo, while the inhibitory effect could be reversed by METTL3 overexpression. Mechanism study indicated that miR-186/METTL3 axis contributed to the progression of HB via the Wnt/β-catenin signalling pathway.ConclusionsM6A-related genes were frequently dysregulated in HB. miR-186/METTL3/Wnt/β-catenin axis might serve as novel therapeutic targets and prognostic biomarkers in HB.
| S-EPMC7106953 | biostudies-literature
Project description:Aberrant activation of the Wnt/β-catenin pathway and polo-like kinase 1 (Plk1) overexpression represent two common events in prostate cancer with relevant functional implications. This minireview analyzes their potential therapeutic significance in prostate cancer based on their role as androgen receptor (AR) signaling regulators and the pivotal role of the tumor suppressor protein phosphatase 2A (PP2A) modulating these pathways.
| S-EPMC4907099 | biostudies-literature
Project description:Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about the relevance of TRIM31 in acute myeloid leukemia (AML). Herein, we investigated the role of TRIM31 in AML. We examined the expression levels of TRIM31 in the blood samples from 34 patients with AML and 34 healthy volunteers using qRT-PCR. The mRNA levels of TRIM31 in human bone marrow stromal cells (HS-5) and five AML cell lines were also detected. Loss/gain-of-function assays were performed to assess the role of TRIM31 in AML cells proliferation, apoptosis and sensitivity to daunorubicin. The expression levels of pro-caspase 3, cleaved caspase 3, Wnt3a, β-catenin, cyclin D1 and c-Myc were measured using Western blot. TRIM31 expression levels were significantly up-regulated in AML patients and cell lines. Knockdown of TRIM31 suppressed cell proliferation and promoted apoptosis in AML-5 and U937 cells. The IC50 of daunorubicin was significantly decreased in TRIM31 siRNA (si-TRIM31) transfected cells. Oppositely, induced cell proliferation and decreased cell apoptosis were observed in pcDNA-3.1-TRIM31 transfected cells. Furthermore, knockdown of TRIM31 suppressed the activation of Wnt/β-catenin pathway in AML cells. Activation of Wnt/β-catenin pathway by LiCl abolished the effects of si-TRIM31 on cell proliferation, apoptosis and sensitivity to daunorubicin in AML cells. In conclusion, the results indicated that TRIM31 promoted leukemogenesis and chemoresistance to daunorubicin in AML. The oncogenic role of TRIM31 in AML was mediated by the Wnt/β-catenin pathway. Thus, TRIM31 might serve as a therapeutic target for the AML treatment.
| S-EPMC7160243 | biostudies-literature
Project description:BackgroundOvarian cancer is the most lethal gynecologic malignancy worldwide. Olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), is becoming widely used in ovarian cancer treatment. The overall survival of ovarian cancer has not been significantly changed over the past decades and ovarian cancer has become increasingly resistant to the Olaparib. Ubiquitin-conjugating enzyme E2S (UBE2S) has been proved to promote malignant behaviors in many cancers. However, the function of UBE2S in the development and Olaparib resistance of ovarian cancer are unclear.Materials and methodsIn this study, we detected the expression of UBE2S in normal fallopian tube (FT) and HGSOC tissues. A2780 and SKOV3 cells were stably transfected with PCMV-UBE2S, PCMV-UBE2S-C95S, UBE2S shRNAs, and negative controls. The CCK8 assay and clonogenic assay were conducted to analyze ovarian cancer proliferation and Olaparib resistance. The transwell assay was performed to determine the migration and invasion of ovarian cancer cells. The relative protein levels of the Wnt/β-catenin signaling pathway were tested using western blot. The ovarian cancer cells were treated with XAV-939 to investigate the role of Wnt/β-catenin signaling pathway in Olaparib resistance. Moreover, we repeated some above procedures in the xenograft model.ResultsThe results demonstrated that UBE2S was highly upregulated in HGSOC and that high UBE2S expression was correlated with poor outcomes in HGSOC. UBE2S promoted ovarian cancer proliferation and drived the migration and invasion of ovarian cancer cells. UBE2S activated the Wnt/β-catenin signaling pathway in ovarian cancer resulting in Olaparib resistance in vitro and in vivo. Furthermore, UBE2S enhanced the proliferation and Olaparib resistance of ovarian cancer in its enzymatic activity dependent manner.ConclusionsThese data suggest a possible molecular mechanism of proliferation and metastasis of ovarian cancer and highlight the potential role of UBE2S as a therapeutic target in ovarian cancer.
| S-EPMC8447717 | biostudies-literature
Project description:BackgroundGlioblastoma (GBM) is a deadly neoplasm of the central nervous system. The molecular mechanisms and players that contribute to GBM development is incompletely understood.MethodsThe expression of PELP1 in different grades of glioma and normal brain tissues was analyzed using immunohistochemistry on a tumor tissue array. PELP1 expression in established and primary GBM cell lines was analyzed by Western blotting. The effect of PELP1 knockdown was studied using cell proliferation, colony formation, migration, and invasion assays. Mechanistic studies were conducted using RNA-seq, RT-qPCR, immunoprecipitation, reporter gene assays, and signaling analysis. Mouse orthotopic models were used for preclinical evaluation of PELP1 knock down.ResultsNuclear receptor coregulator PELP1 is highly expressed in gliomas compared to normal brain tissues, with the highest expression in GBM. PELP1 expression was elevated in established and patient-derived GBM cell lines compared to normal astrocytes. Knockdown of PELP1 resulted in a significant decrease in cell viability, survival, migration, and invasion. Global RNA-sequencing studies demonstrated that PELP1 knockdown significantly reduced the expression of genes involved in the Wnt/β-catenin pathway. Mechanistic studies demonstrated that PELP1 interacts with and functions as a coactivator of β-catenin. Knockdown of PELP1 resulted in a significant increase in survival of mice implanted with U87 and GBM PDX models.ConclusionsPELP1 expression is upregulated in GBM and PELP1 signaling via β-catenin axis contributes to GBM progression. Thus, PELP1 could be a potential target for the development of therapeutic intervention in GBM.
| S-EPMC7147719 | biostudies-literature
Project description:Dysregulated Wnt/β-catenin activation plays a critical role in cancer progression, metastasis, and drug resistance. Genotoxic agents such as radiation and chemotherapeutics have been shown to activate the Wnt/β-catenin signaling although the underlying mechanism remains incompletely understood. Here, we show that genotoxic agent-activated Wnt/β-catenin signaling is independent of the FZD/LRP heterodimeric receptors and Wnt ligands. OTULIN, a linear linkage-specific deubiquitinase, is essential for the DNA damage-induced β-catenin activation. OTULIN inhibits linear ubiquitination of β-catenin, which attenuates its Lys48-linked ubiquitination and proteasomal degradation upon DNA damage. The association with β-catenin is enhanced by OTULIN Tyr56 phosphorylation, which depends on genotoxic stress-activated ABL1/c-Abl. Inhibiting OTULIN or Wnt/β-catenin sensitizes triple-negative breast cancer xenograft tumors to chemotherapeutics and reduces metastasis. Increased OTULIN levels are associated with aggressive molecular subtypes and poor survival in breast cancer patients. Thus, OTULIN-mediated Wnt/β-catenin activation upon genotoxic treatments promotes drug resistance and metastasis in breast cancers.
| S-EPMC7414915 | biostudies-literature
Project description:The canonical Wnt/β-catenin signalling pathway plays a crucial role in a variety of functions including cell proliferation and differentiation, tumorigenic processes and radioresistance in cancer cells. The Mre11-Rad50-Nbs1 (MRN) complex has a pivotal role in sensing and repairing DNA damage. However, it remains unclear whether a connection exists between Wnt/β-catenin signalling and the MRN complex in the repair of cisplatin-induced DNA interstrand cross-links (ICLs). Here, we report that (1) cisplatin exposure results in a significant increase in the levels of MRN complex subunits in human tumour cells; (2) cisplatin treatment stimulates Wnt/β-catenin signalling through increased β-catenin expression; (3) the functional perturbation of Wnt/β-catenin signalling results in aberrant cell cycle dynamics and the activation of DNA damage response and apoptosis; (4) a treatment with CHIR99021, a potent and selective GSK3β inhibitor, augments cisplatin-induced cell death in cancer cells. On the other hand, inactivation of the Wnt/β-catenin signalling with FH535 promotes cell survival. Consistently, the staining pattern of γH2AX-foci is significantly reduced in the cells exposed simultaneously to cisplatin and FH535; and (5) inhibition of Wnt/β-catenin signalling impedes cisplatin-induced phosphorylation of Chk1, abrogates the G2/M phase arrest and impairs recombination-based DNA repair. Our data further show that Wnt signalling positively regulates the expression of β-catenin, Mre11 and FANCD2 at early time points, but declining thereafter due to negative feedback regulation. These results support a model wherein Wnt/β-catenin signalling and MRN complex crosstalk during DNA ICL repair, thereby playing an important role in the maintenance of genome stability.
| S-EPMC7646826 | biostudies-literature
Project description:BackgroundBreast cancer (BrCa) is the most common female malignancy worldwide and has the highest morbidity among all cancers in females. Unfortunately, the mechanisms of BrCa growth and metastasis, which lead to a poor prognosis in BrCa patients, have not been well characterized.MethodsImmunohistochemistry (IHC) was performed on a BrCa tissue microarray (TMA) containing 80 samples to evaluate ubiquitin protein ligase E3C (UBE3C) expression. In addition, a series of cellular experiments were conducted to reveal the role of UBE3C in BrCa.ResultsIn this research, we identified UBE3C as an oncogenic factor in BrCa growth and metastasis for the first time. UBE3C expression was upregulated in BrCa tissues compared with adjacent breast tissues. BrCa patients with high nuclear UBE3C expression in tumors showed remarkably worse overall survival (OS) than those with low nuclear expression. Knockdown of UBE3C expression in MCF-7 and MDA-MB-453 BrCa cells inhibited cell proliferation, migration and invasion in vitro, while overexpression of UBE3C in these cells exerted the opposite effects. Moreover, UBE3C promoted β-catenin nuclear accumulation, leading to the activation of the Wnt/β-catenin signaling pathway in BrCa cells.ConclusionCollectively, these results imply that UBE3C plays crucial roles in BrCa development and progression and that UBE3C may be a novel target for the prevention and treatment of BrCa.
| S-EPMC7789303 | biostudies-literature
Project description:Globally, ovarian cancer is the 2nd most frequent cause of gynecologic-associated cancer fatalities among women. It has an unfavorable prognosis. There is a need to elucidate on the mechanisms involved in ovarian cancer progression and to identify novel cancer targets. We investigated and verified AHNAK contents in ovarian cancer tissues and corresponding healthy tissues. Then, we overexpressed AHNAK in vitro and in vivo to establish the roles of AHNAK in ovarian cancer cell proliferation and metastasis. Finally, we evaluated the possible molecular mechanisms underlying. We established that AHNAK was downregulated in ovarian cancer. Elevated AHNAK contents in ovarian cancer cell lines remarkably repressed ovarian cancer cell growth, along with metastasis in vitro, as well as in vivo. Moreover, AHNAK suppressed the progress of ovarian cancer partly via dampening the Canonical Wnt cascade. Therefore, AHNAK may be a biomarker and treatment target for ovarian cancer.
| S-EPMC8580348 | biostudies-literature
Project description:BackgroundAlthough there are many treatments for breast cancer, such as surgery, radiotherapy, chemotherapy, estrogen receptor antagonists, immune checkpoint inhibitors and so on. However, safer and more effective therapeutic drugs for breast cancer are needed. Sinensetin, a safer therapeutic drugs, come from citrus species and medicinal plants used in traditional medicine, while its role and underlying mechanism in breast cancer remain unclear. Our study aimed to investigate the role and mechanism of sinensetin in breast cancer.MethodsCell Counting Kit-8 (CCK-8) was used to determine the safe concentration of sinensetin in MCF-10A, MCF7 and MDA-MB-231 cells; 120 μM sinensetin was used in subsequent experiments. Real time polymerase chain reaction (RT-PCR), Western blotting, Terminal Deoxynucleotidyl Transferase mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay, Transwell invasion assay and Clone formation assay were used in this study to determine cell viability, mRNA expression, protein levels, apoptosis, proliferation, invasion and so on.ResultsHerein, our results showed that 120 μM sinensetin suppressed the cell viability and promoted apoptosis of MCF7 and MDA-MB-231 cells. Treatment with 120 µM sinensetin for 24 h showed no significant toxicity to normal mammary cells; 120 μM sinensetin decreased cell proliferation, invasion, and epithelial-mesenchymal transition (EMT), and downregulated β-catenin, lymphatic enhancing factor 1 (LEF1), T-cell factor (TCF) 1/TCF7, and TCF3/TCF7L1 expression in MCF7 and MDA-MB-231 cells. The Wnt agonist SKL2001 reversed the inhibitory effect of sinensetin on cell survival, metastasis, and EMT. Sinensetin-induced downregulation of β-catenin, LEF1, and TCF1/TCF7 expression were upregulated by SKL2001 in MCF7 and MDA-MB-231 cells.ConclusionsIn summary, sinensetin suppressed the metastasis of breast cancer cell via inhibition of Wnt/β-catenin pathway and there were no adverse effects on normal breast cells. Our study confirmed the role of sinensetin in breast cancer cells and provided a better understanding of the underlying mechanism.
| S-EPMC10894327 | biostudies-literature